EP3481839B1 - Procédé de purification de méthylcobalamine - Google Patents
Procédé de purification de méthylcobalamine Download PDFInfo
- Publication number
- EP3481839B1 EP3481839B1 EP17714232.0A EP17714232A EP3481839B1 EP 3481839 B1 EP3481839 B1 EP 3481839B1 EP 17714232 A EP17714232 A EP 17714232A EP 3481839 B1 EP3481839 B1 EP 3481839B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methylcobalamin
- iron
- resin
- process according
- cyanide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 title claims description 81
- 239000011585 methylcobalamin Substances 0.000 title claims description 81
- 235000007672 methylcobalamin Nutrition 0.000 title claims description 81
- 238000000034 method Methods 0.000 title claims description 50
- 238000000746 purification Methods 0.000 title claims description 19
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 claims description 58
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 46
- -1 iron cyanide anions Chemical class 0.000 claims description 39
- 239000011347 resin Substances 0.000 claims description 39
- 229920005989 resin Polymers 0.000 claims description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 30
- 239000011666 cyanocobalamin Substances 0.000 claims description 29
- 229960002104 cyanocobalamin Drugs 0.000 claims description 29
- 239000003957 anion exchange resin Substances 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052742 iron Inorganic materials 0.000 claims description 18
- 239000012535 impurity Substances 0.000 claims description 16
- 238000006485 reductive methylation reaction Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 15
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 13
- PANJMBIFGCKWBY-UHFFFAOYSA-N iron tricyanide Chemical compound N#C[Fe](C#N)C#N PANJMBIFGCKWBY-UHFFFAOYSA-N 0.000 claims description 11
- MYRTYDVEIRVNKP-UHFFFAOYSA-N divinylbenzene Substances C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 9
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 7
- 239000006184 cosolvent Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 5
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 31
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 26
- 239000007864 aqueous solution Substances 0.000 description 11
- 150000001450 anions Chemical class 0.000 description 10
- 239000012022 methylating agents Substances 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000001867 cobalamins Chemical class 0.000 description 7
- 229940010007 cobalamins Drugs 0.000 description 7
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000001636 atomic emission spectroscopy Methods 0.000 description 5
- 229920001429 chelating resin Polymers 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000009616 inductively coupled plasma Methods 0.000 description 5
- 239000002516 radical scavenger Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000011715 vitamin B12 Substances 0.000 description 5
- NAVJNPDLSKEXSP-UHFFFAOYSA-N Fe(CN)2 Chemical class N#C[Fe]C#N NAVJNPDLSKEXSP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KEPJZBFFLDRKSF-UHFFFAOYSA-M trimethylsulfoxonium bromide Chemical compound [Br-].C[S+](C)(C)=O KEPJZBFFLDRKSF-UHFFFAOYSA-M 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 159000000014 iron salts Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 230000001035 methylating effect Effects 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- OAJLVMGLJZXSGX-NDSREFPTSA-L (2r,3s,4s,5r)-2-(6-aminopurin-9-yl)-5-methanidyloxolane-3,4-diol;cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12 Chemical compound [Co+3].O[C@H]1[C@H](O)[C@@H]([CH2-])O[C@H]1N1C2=NC=NC(N)=C2N=C1.C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O OAJLVMGLJZXSGX-NDSREFPTSA-L 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- POYMFKJUYZDXAT-UHFFFAOYSA-N 1-(4-iodophenyl)pyrrolidine Chemical compound C1=CC(I)=CC=C1N1CCCC1 POYMFKJUYZDXAT-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- GLVPUAWFPNGKHO-UHFFFAOYSA-L N.[Fe+2].[O-]S([O-])(=O)=O Chemical compound N.[Fe+2].[O-]S([O-])(=O)=O GLVPUAWFPNGKHO-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- FEZWOUWWJOYMLT-DSRCUDDDSA-M cobalt;[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7,1 Chemical compound [Co].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FEZWOUWWJOYMLT-DSRCUDDDSA-M 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- WUPRCGRRQUZFAB-DEGKJRJSSA-N corrin Chemical group N1C2CC\C1=C\C(CC/1)=N\C\1=C/C(CC\1)=N/C/1=C\C1=NC2CC1 WUPRCGRRQUZFAB-DEGKJRJSSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 description 2
- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- GOTIICCWNAPLMN-UHFFFAOYSA-M trimethylsulfanium;bromide Chemical compound [Br-].C[S+](C)C GOTIICCWNAPLMN-UHFFFAOYSA-M 0.000 description 2
- OWUGVJBQKGQQKJ-UHFFFAOYSA-M trimethylsulfanium;chloride Chemical compound [Cl-].C[S+](C)C OWUGVJBQKGQQKJ-UHFFFAOYSA-M 0.000 description 2
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 2
- ZXHDVRATSGZISC-UHFFFAOYSA-N 1,2-bis(ethenoxy)ethane Chemical compound C=COCCOC=C ZXHDVRATSGZISC-UHFFFAOYSA-N 0.000 description 1
- SAMJGBVVQUEMGC-UHFFFAOYSA-N 1-ethenoxy-2-(2-ethenoxyethoxy)ethane Chemical compound C=COCCOCCOC=C SAMJGBVVQUEMGC-UHFFFAOYSA-N 0.000 description 1
- GNENVASJJIUNER-UHFFFAOYSA-N 2,4,6-tricyclohexyloxy-1,3,5,2,4,6-trioxatriborinane Chemical compound C1CCCCC1OB1OB(OC2CCCCC2)OB(OC2CCCCC2)O1 GNENVASJJIUNER-UHFFFAOYSA-N 0.000 description 1
- NYXKVDPOWQTTNC-UHFFFAOYSA-N 2,4-dimethyl-1h-benzimidazole Chemical group C1=CC=C2NC(C)=NC2=C1C NYXKVDPOWQTTNC-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical group NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- CPKISUMKCULUNR-UHFFFAOYSA-N 2-methoxy-2-oxoacetic acid Chemical compound COC(=O)C(O)=O CPKISUMKCULUNR-UHFFFAOYSA-N 0.000 description 1
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 description 1
- 102000011848 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Human genes 0.000 description 1
- 108010075604 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Proteins 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 102000019010 Methylmalonyl-CoA Mutase Human genes 0.000 description 1
- 108010051862 Methylmalonyl-CoA mutase Proteins 0.000 description 1
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 1
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001918 cyanocobalamins Chemical class 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 0.000 description 1
- 229960001103 hydroxocobalamin Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ANXKZXRDXAZQJT-UHFFFAOYSA-M methyl sulfate;trimethylsulfanium Chemical compound C[S+](C)C.COS([O-])(=O)=O ANXKZXRDXAZQJT-UHFFFAOYSA-M 0.000 description 1
- 230000007658 neurological function Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000007539 photo-oxidation reaction Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- YRYSAWZMIRQUBO-UHFFFAOYSA-N trimethylsulfoxonium Chemical compound C[S+](C)(C)=O YRYSAWZMIRQUBO-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Definitions
- the present invention relates to a process for the purification of methylcobalamin, which is one of the coenzyme forms of vitamin B 12 .
- Cobalamins are a group of closely related and interconvertible cobalt coordination compounds, which are usually collectively known as vitamin B 12 .
- Cobalamins belong to the family of corrinoids, which share a planar tetrapyrrolic ring (corrin ring) containing a central cobalt atom, which may assume an oxidation state of (I), (II) or (III). Additionally, cobalamins possess an upper (beta) and a lower (alpha) axial ligands, as represented in the following structure:
- the lower ligand (alpha) is the dimethylbenzimidazole group of a nucleotide, which is connected to the corrin ring through an amide bond.
- the beta ligand (R) may be a cyano-, hydroxo-, methyl- or 5'-deoxyadenosyl- group, giving rise, respectively, to cyanocobalamin, hydroxocobalamin, methylcobalamin, and 5'-deoxyadenosylcobalamin.
- vitamin B 12 refers specifically to cyanocobalamin, i.e., when R is the cyano group (CN).
- methylcobalamin and 5'-deoxyadenosylcobalamin are the active forms that function as coenzymes for metabolic reactions in the organism, namely in those reactions catalysed by the enzymes methionine synthase and methylmalonyl-CoA mutase, which are related, for example, to red blood cell formation, neurological function, and DNA synthesis. Consequently, vitamin B 12 deficiency is associated with several pathologies, such as megaloblastic anaemia, fatigue, weakness, constipation, loss of appetite, weight loss, and neurological disorders. In such deficiency states, the administration of cobalamins is indicated.
- Methylcobalamin in particular, is successfully used in therapy for treating several disorders associated to vitamin B 12 deficiency, for example, for treating peripheral neuropathy or megaloblastic anaemia.
- Methylcobalamin is commonly obtained from cyanocobalamin, by means of a reductive methylation process, involving the treatment of cyanocobalamin with a reducing agent and with a methylating agent.
- a reductive methylation process involving the treatment of cyanocobalamin with a reducing agent and with a methylating agent.
- the cyanide anions which are released from cyanocobalamin during the reduction reaction, tend to bond again to the reduced form of cobalamin, known as cob(I)alamin or vitamin B 12S , competing with the methylating agent and, thus, lowering the overall reaction yield of the process.
- this reaction can be advantageously performed in the presence of an agent able to act as cyanide scavenger, i.e., by complexing the cyanide anions present in the reaction media and thus avoiding any interference with the methylation process.
- an agent able to act as cyanide scavenger i.e., by complexing the cyanide anions present in the reaction media and thus avoiding any interference with the methylation process.
- metallic salts particularly, iron (II) salts.
- GB 1419933 discloses the preparation of methylcobalamin by reductive methylation of cyanocobalamin using monomethyl oxalate and zinc as methylating agents and using cobalt chloride as a catalyst.
- Methylcobalamin was dissolved in an acetone aqueous solution and purified using cation and anion exchange resins were used. After purification, acetone was added and the solution was left to crystallise to yield methylcobalamin.
- the European patent application EP1236737-A1 discloses the preparation of methylcobalamin by reductive methylation of cyanocobalamin using trimethylsulfoxonium or trimethylsulfonium halide salts as methylating agents and using iron (II) sulphate heptahydrate and/or cobalt (II) chloride hexahydrate as cyanide scavenging agents.
- iron salts which are efficient for improving the performance of the reductive methylation process, may lead to iron residues in the final pharmaceutical substance, and consequently in the final drug product.
- the object of the present invention is a process for the purification of methylcobalamin.
- the object of the present invention is a process for the purification of methylcobalamin from mixtures with iron cyanide anions characterized in that it comprises contacting a solution comprising methylcobalamin and iron cyanide anions with a strongly basic anion exchange resin.
- the authors of the present invention have developed a new process for the purification of methylcobalamin based on the treatment with a strongly basic anion exchange resin, which, surprisingly, allows the efficient removal of traces of iron cyanide anions present in methylcobalamin solutions using a simple process which can be easily industrially implemented to provide methylcobalamin with a reduced iron content.
- This process can advantageously be used for removing iron cyanide impurities from methylcobalamin obtained by reductive methylation of cyanocobalamin wherein iron (II) salts are used as cyanide scavengers, thus providing methylcobalamin with a reduced iron content.
- An anion exchange resin as is well known in the art, is an insoluble polymeric matrix containing anions which are able to be exchanged with other anions in solutions which come in contact with them.
- a strongly basic anion exchange resin is a particular type of anion exchange resin wherein the anion which is exchanged is the counterion of a quaternary ammonium group which is bound to the polymeric matrix of the resin, typically a trialkylammonium group such as trimethylammonium, or a dialkyl 2-hydroxyethyl ammonium group.
- the resin has trialkylammonium functional groups, more preferably trimethylammonium groups.
- the counterion which is exchanged, is generally a chloride or a hydroxide anion.
- the counterion is a chloride anion.
- the polymeric matrix of the resin can be a crosslinked polystyrene-divinylbenzene polymer, i.e., prepared from styrene and divinylbenzene as cross-linking agent; or can be a crosslinked acrylic polymer, prepared from acrylic acid, methacrylic acid, or esters of acrylic or methacrylic acid, e.g. methyl, ethyl, or propyl esters, crosslinked with e.g. divinylbenzene, ethyleneglycol dimethacrylate, ethyleneglycol divinyl ether, or diethyleneglycol divinyl ether.
- the resin is selected from a crosslinked polystyrene-divinylbenzene resin and a crosslinked acrylic-divinylbenzene resin.
- the resin is a crosslinked acrylic-divinylbenzene resin.
- the resins are generally available in form of beads. According to its porosity, the resin can be microporous (gel-type) or macroporous (macroreticular). Preferably, the resin has macroreticular structure.
- the strongly basic anion exchange resin is a resin having trialkylammonium functional groups and interchanging chloride anions. More preferably, the resin is a crosslinked acrylic-divinylbenzene resin having macroreticular structure.
- a number of strongly basic anion exchange resins suitable to be used in the process of the present invention are commercially available, for example, Amberlite ® IRA458 RF Cl, Amberlite ® IRA900 Cl, Amberlite ® IRA958 Cl; Diaion ® SA10A(CI), Diaion ® HPA25(CI), Dowex ® Marathon A, Dowex ® Marathon MSA, Lewatit ® MonoPlus MP500, Lewatit ® MonoPlus MP800, or the strongly basic anion exchange resins from the company Purolite, for example of the Purolite ® A200 or Purolite ® A500 series; among others.
- Amberlite ® IRA958 CI is particularly preferred. It is a macroreticular, strongly basic anion exchange resin having quaternary ammonium functionality in a crosslinked acrylic polymer matrix and interchanging chloride anions.
- the purification process according to the present invention can advantageously be used for removing iron cyanide impurities from methylcobalamin obtained by reductive methylation of cyanocobalamin wherein iron (II) salts are used as cyanide scavengers.
- This purification process is particularly useful for removing residual amounts, namely trace amounts, of iron cyanide anions which still remain as impurities of methylcobalamin, even after having removed a large proportion of the iron cyanide formed in the process by filtering off insoluble iron cyanide salts.
- the amount of residual iron cyanide impurities contained in methylcobalamin, which are to be removed with the process of the current invention by treatment with the resin is generally equivalent to less than 6000 ppm of iron, preferably less than 5000 ppm of iron, more preferably less than 4000 ppm of iron, and still more preferably less than 1600 ppm.
- the process of contacting the solution comprising methylcobalamin and iron cyanide anions with the strongly basic anion exchange resin is preferably performed by passing the solution through an effective amount of the resin.
- a column is filled with an adequate amount of the resin and the solution comprising methylcobalamin and iron cyanide anions is passed through it, either in down-flow or in upper-flow, and the resulting solution is subsequently collected.
- the solution is passed in upper-flow.
- the solution is passed through the resin over a certain period of time, generally comprised between 2 and 6 hours, and more preferably comprised between 3 and 4 hours.
- the strongly basic anion exchange resin is used in a weight ratio resin:methylcobalamin generally comprised between 0.1:1 and 2:1, and more preferably comprised between 0.3:1 and 1:1.
- the weight ratio resin:methylcobalamin is approximately 0.5:1.
- an amount of solvent alone is subsequently passed through the resin to collect the methylcobalamin that can remain within the resin.
- the iron cyanide anions present in the solution are retained by the resin, while the counterion of the resin, typically the chloride anion, is in turn released.
- iron cyanide anions are meant to be anionic iron (II) or iron (III) complexes with cyanide.
- iron cyanide anions typically, among the iron cyanide anions are the ferrocyanide anions, also known as hexacyanoferrate (II) anions ([Fe(CN) 6 ] 4- ) and the ferricyanide anions, also known as hexacyanoferrate (III) anions ([Fe(CN) 6 ] 3- ).
- the iron cyanide anions present as impurities of methylcobalamin may be a mixture of different iron cyanide complexes.
- the anion interchange that takes place between the anion exchange resin and the ferrocyanide anions can be represented as follows:
- Example 3 the methylcobalamin obtained by reductive methylation of cyanocobalamin using iron salts as cyanide-scavengers could be effectively separated from iron cyanide impurities using the method of the present invention, thus obtaining methylcobalamin having less than 130 ppm of iron, namely 71 ppm or even less than 30 ppm, whereas when the same process was performed without using a strongly basic anion exchange resin, the level of iron in methylcobalamin was much higher, 494 or 1594 ppm.
- the anion exchange resin Upon usage, the anion exchange resin progressively loses its capacity of anion exchanging, as more iron cyanide anions get retained into it.
- the exhausted resin can be regenerated with an aqueous solution of a salt of the resin counterion, preferably an aqueous solution of a chloride salt, more preferably an aqueous solution of sodium chloride.
- the solvent used for performing the purification process, in which methylcobalamin and the iron cyanide anions are dissolved can be water or a mixture of water with a water-miscible organic co-solvent.
- Suitable organic co-solvents include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, or tert-butanol; ketones such as acetone or 2-butanone; ethers such as 1,4-dioxane, tetrahydrofuran, dimethoxyethane or diglyme; and mixtures thereof.
- the solvent is a mixture of water and a water-miscible organic co-solvent, preferably a mixture of water and a water-miscible co-solvent selected from an alcohol, a ketone, and mixtures thereof; more preferably the solvent is a mixture of water and a water-miscible ketone, and still more preferably is a mixture of water and acetone.
- the volume proportion water:organic solvent is generally comprised between 1.8:1 and 1:1.5, preferably comprised between 1.5:1 and 1:1.2, more preferably comprised between 1.1:1 and 1:1.1.
- the solvent is a mixture of water and acetone in approximately 1:1 volume proportion.
- the solution containing methylcobalamin and the iron cyanide impurities which is contacted with the anion exchange resin comprises methylcobalamin in a concentration generally comprised between 30-150 g/L, preferably between 40-100 g/L, and more preferably comprised between 50-75 g/L.
- methylcobalamin can be isolated by crystallizing or precipitating it from the solution, generally adding a ketone solvent to the solution, preferably adding acetone to the solution.
- the solution which is subjected to the purification process is prepared by treating the crude methylcobalamin comprising iron cyanide impurities with the solvent and heating to a temperature comprised between 30° C and 60° C, preferably between 40° C and 50° C, and more preferably at approximately 45° C, during a period of time generally comprised between 15 and 60 minutes.
- the suspension thus obtained is generally filtered to remove the insoluble impurities, for example, insoluble iron cyanide salts, and the filtered solution, still containing residual iron cyanide anions, is then contacted with the strongly basic anion exchange resin, according to the process of the invention.
- the purification of methylcobalamin comprises the following steps:
- the methylcobalamin obtained after performing the process of the invention has a reduced iron content, namely, the amount of iron is less than 130 ppm, preferably less than 90 ppm, still more preferably less than 80 ppm, and still more preferably less than 70 ppm of iron.
- the determination of the iron amount can be performed, for example, by inductively coupled plasma optical emission spectrometry (ICP/OES).
- ICP/OES inductively coupled plasma optical emission spectrometry
- Another aspect of the present invention is the use of a strongly basic anion exchange resin for removing iron cyanide anions from methylcobalamin.
- the methylcobalamin containing iron cyanide impurities which is susceptible to be purified with the process of the invention, is typically the result of a reductive methylation reaction of cyanocobalamin, performed in the presence of iron (II) salts and optionally iron (III) salts as cyanide scavengers.
- the reductive methylation of cyanocobalamin is typically carried out by treatment of cyanocobalamin with a reducing agent and a methylating agent.
- cyanocobalamin ( CAS number 68-19-9 ) is commercially available from several sources.
- the reducing agent can be any agent capable of reducing the cobalt of cyanocobalamins from Co(lll) to Co(I).
- Suitable reducing agents are, for example, alkaline metal borohydrides.
- a preferred reducing agent is sodium borohydride.
- the amount of reducing agent is not particularly limited, but is generally comprised between 5 and 30 equivalents, preferably between 10 and 20 equivalents to cyanocobalamin.
- methylating agent can be employed, for example, trimethylsulfonium bromide, trimethylsulfonium chloride, trimethylsulfonium methylsulphate, trimethylsulfoxonium chloride, trimethylsulfoxonium iodide, trimethylsulfoxonium bromide, dimethyl carbonate, dimethyl sulphate, tetramethylammonium chloride or methyl iodide.
- the methylating agent is selected from the group consisting of trimethylsulfonium bromide, trimethylsulfonium chloride, trimethylsulfoxonium chloride, trimethylsulfoxonium iodide, trimethylsulfoxonium bromide and dimethyl carbonate.
- the amount of methylating agent employed is generally comprised between 1 and 10 equivalents, preferably between 2 and 5 equivalents to cyanocobalamin.
- the reductive methylation reaction is performed in aqueous media, optionally in combination with a water-miscible organic co-solvent.
- suitable co-solvents are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, or tert- butanol; ketones such as acetone or 2-butanone; ethers such as 1,4-dioxane, tetrahydrofuran, dimethoxyethane or diglyme; amides such as dimethylformamide, or dimethylacetamide; and mixtures thereof.
- co-solvents preferably alcohols or ketones are used.
- the reaction is preferably carried out at slightly basic pH, e.g. 7.5-8.5, and at a temperature in the range 5-60° C, preferably in the range 20-40° C.
- An iron (II) salt is added to the reaction as cyanide scavenger, for example, iron (II) sulphate, iron (II) chloride, or ammonium iron (II) sulphate (Mohr's salt).
- the cyanide ions released in the reduction reaction are complexed by the iron (II) cation to form anionic iron (II) cyanide complexes, for example, the ferrocyanide complex [Fe(CN) 6 ] 4- , thus avoiding that they interfere with the methylation process.
- the iron (II) salt is employed in an amount generally comprised between 0.5 and 1.5 equivalents to cyanocobalamin, and preferably approximately 1 equivalent of iron (II) salt to cyanocobalamin is employed.
- an iron (III) salt is also added, typically to form insoluble salts with the ferrocyanide anion, thus allowing their simple removal by filtration.
- the reaction is generally performed by dissolving cyanocobalamin, an iron (II) salt, and optionally an iron (III) salt, and adding, sequentially or simultaneously, the reducing agent and the methylating agent.
- Cyanocobalamin and methylcobalamin solutions are known to be susceptible photo-oxidation, therefore, the reductive methylation process is preferably performed under inert atmosphere, for example under flow of an inert gas such as nitrogen, and in absence of light, under red-light illumination.
- inert atmosphere for example under flow of an inert gas such as nitrogen, and in absence of light, under red-light illumination.
- methylcobalamin is generally precipitated from the reaction mixture, by cooling the reaction media, typically also adding further organic solvent, and filtering the crude methylcobalamin.
- the crude methylcobalamin thus obtained contains salts containing iron cyanide anions, and can be then purified using the process of the present invention, so it is made into a solution, by treating it with a suitable solvent, as disclosed above.
- the content of iron impurity in the methylcobalamin was less than 30 ppm, determined by inductively coupled plasma/optical emission spectrometry (ICP/OES).
- a second batch (batch B) and third batch (batch C) of methylcobalamin were prepared according to the same processes a) and b) disclosed above. Methylcobalamin was obtained in a yield of 84.4% and 87.9%, respectively, and the iron content was 71 ppm and less than 30 ppm, respectively.
- the content of iron impurity in the methylcobalamin was 494 ppm, determined by inductively coupled plasma/optical emission spectrometry (ICP/OES).
- a second batch (batch 2) of methylcobalamin was prepared according to the same process disclosed above. Methylcobalamin was obtained in a yield of 86.7%, and the iron content was 1594 ppm.
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- Biochemistry (AREA)
- Biotechnology (AREA)
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Claims (14)
- Procédé de purification de méthylcobalamine (I)
- Procédé selon la revendication 1, caractérisé en ce que la résine échangeuse d'anions fortement basique a des groupes fonctionnels trialkyl ammonium et échange des anions chlorure.
- Procédé selon la revendication 1 ou 2, caractérisé en ce que la résine est choisie parmi une résine de type polystyrène-divinylbenzène réticulée et une résine de type acrylique-divinylbenzène réticulée.
- Procédé selon l'une quelconque des revendications 1 à 3, caractérisé en ce que la résine est une résine de type acrylique-divinylbenzène réticulée à structure macroréticulaire.
- Procédé selon l'une quelconque des revendications 1 à 4, caractérisé en ce que le procédé de mise en contact de la solution comprenant de la méthylcobalamine et des anions cyanure de fer avec la résine échangeuse d'anions fortement basique est réalisé en faisant passer la solution à travers une quantité efficace de la résine sur une durée de temps comprise entre 2 et 6 heures.
- Procédé selon l'une quelconque des revendications 1 à 5, caractérisé en ce que le rapport de poids résine: méthylcobalamine est compris entre 0,1 : 1 et 2 : 1.
- Procédé selon la revendication 6, caractérisé en ce que le rapport de poids résine: méthylcobalamine est d'environ 0,5 : 1.
- Procédé selon l'une quelconque des revendications 1 à 7, caractérisé en ce que le solvant utilisé dans la solution est choisi parmi l'eau et un mélange d'eau avec un co-solvant organique miscible à l'eau.
- Procédé selon la revendication 8, caractérisé en ce que le solvant est un mélange d'eau et un co-solvant organique miscible à l'eau.
- Procédé selon la revendication 9, caractérisé en ce que le solvant est un mélange d'eau et acétone.
- Procédé selon les revendications 9 ou 10, caractérisé en ce que le rapport volumique eau: co-solvant organique est compris entre 1,8 : 1 et 1 : 1,5.
- Procédé selon l'une quelconque des revendications 1 à 11 , caractérisé en ce que la méthylcobalamine est cristallisée à partir de la solution recueillie après le traitement avec la résine.
- Procédé selon l'une quelconque des revendications 1 à 12, caractérisé en ce que la solution qui est soumise au procédé de purification est préparée en traitant de la méthylcobalamine comprenant des impuretés de cyanure de fer avec le solvant, en chauffant à une température comprise entre 30°C et 60°C, et filtrant pour enlever les impuretés insolubles.
- Procédé selon l'une quelconque des revendications 1 à 13, caractérisé en ce que la méthylcobalamine obtenue a une teneur en fer de moins de 130 ppm.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP16178560 | 2016-07-08 | ||
PCT/EP2017/057506 WO2018007035A1 (fr) | 2016-07-08 | 2017-03-30 | Procédé de purification de méthylcobalamine |
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EP3481839A1 EP3481839A1 (fr) | 2019-05-15 |
EP3481839B1 true EP3481839B1 (fr) | 2023-06-07 |
EP3481839C0 EP3481839C0 (fr) | 2023-06-07 |
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US (1) | US11059851B2 (fr) |
EP (1) | EP3481839B1 (fr) |
JP (1) | JP6867409B2 (fr) |
ES (1) | ES2952837T3 (fr) |
HU (1) | HUE063127T2 (fr) |
PL (1) | PL3481839T3 (fr) |
WO (1) | WO2018007035A1 (fr) |
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CN108546278A (zh) * | 2018-03-17 | 2018-09-18 | 山东辰龙药业有限公司 | 甲钴胺的精制方法 |
CN108948116A (zh) * | 2018-08-30 | 2018-12-07 | 上海应用技术大学 | 一种甲钴胺的绿色合成工艺 |
WO2022087656A1 (fr) * | 2020-10-27 | 2022-05-05 | Commonwealth Scientific And Industrial Research Organisation | Procédé d'élimination du cyanure d'un fluide aqueux contenant du cyanure |
CN113959805B (zh) * | 2021-10-25 | 2024-06-21 | 淄博高新技术产业开发区生物医药研究院 | 甲钴胺原料药中氯化钴杂质的分析检测方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS4538059B1 (fr) | 1967-07-27 | 1970-12-02 | ||
BE759614A (fr) | 1969-12-01 | 1971-06-01 | Glaxo Lab Ltd | Elimination d'ions cyanure de solutions de corrinoides |
US3928320A (en) * | 1971-11-10 | 1975-12-23 | Jean Boige | Process for the preparation of methylcobalamine |
NO742545L (fr) * | 1973-08-08 | 1975-03-10 | Opochimie L | |
KR100694688B1 (ko) | 1999-12-09 | 2007-03-13 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 메틸코발라민의 제조 방법 |
EP1394174B1 (fr) * | 2001-06-05 | 2015-11-11 | Eisai R&D Management Co., Ltd. | Procede de production de methylcobalamine |
-
2017
- 2017-03-30 EP EP17714232.0A patent/EP3481839B1/fr active Active
- 2017-03-30 JP JP2018558675A patent/JP6867409B2/ja active Active
- 2017-03-30 HU HUE17714232A patent/HUE063127T2/hu unknown
- 2017-03-30 ES ES17714232T patent/ES2952837T3/es active Active
- 2017-03-30 US US16/311,091 patent/US11059851B2/en active Active
- 2017-03-30 PL PL17714232.0T patent/PL3481839T3/pl unknown
- 2017-03-30 WO PCT/EP2017/057506 patent/WO2018007035A1/fr unknown
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US20200308217A1 (en) | 2020-10-01 |
HUE063127T2 (hu) | 2024-01-28 |
ES2952837T3 (es) | 2023-11-06 |
US11059851B2 (en) | 2021-07-13 |
EP3481839A1 (fr) | 2019-05-15 |
PL3481839T3 (pl) | 2023-10-02 |
JP2019521962A (ja) | 2019-08-08 |
EP3481839C0 (fr) | 2023-06-07 |
JP6867409B2 (ja) | 2021-04-28 |
WO2018007035A1 (fr) | 2018-01-11 |
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